Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([CH:11]([O:16][CH3:17])[C:12]([NH:14][NH2:15])=[O:13])[CH:9]=[CH:10][C:2]1=2.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O>C(O)C.C(O)(=O)C.CCOCC>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([CH:11]([O:16][CH3:17])[C:12]([NH:14]/[N:15]=[CH:23]/[C:22]3[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=3)=[O:13])[CH:9]=[CH:10][C:2]1=2
Reactant: COC(C(=O)NN)c1ccc2c(c1)OCCO2
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(/C=N/NC(=O)C(OC)c2ccc3c(c2)OCCO3)cc(OC)c1OC

Procedure:
In a round-bottom glass flask equipped with a magnetic stir bar 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methoxyacetohydrazide (1 eq., 1.1 mmol; 260 mg) was dissolved in ethanol (10 mL) at room temperature. To this well stirred solution, acetic acid (˜3 drops) and 3,4,5-trimethoxy-benzaldehyde (1.2 eq, 1.3 mmol; 260 mg) were added, and the reaction mixture was heated for 12 hours. The mixture was then cooled and the crude product was diluted with Et2O and filtered and the solid was washed thoroughly with Et2O to yield: 300 mg (65%) of (2-1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:23][O:24][C:25](=[O:39])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]2)=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:23][O:24][C:25](=[O:39])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH:38][C:13](=[O:15])/[C:12](/[C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=3)=[N:16]/[O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:34]2)=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(Cn2ccc(N)n2)cc1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2ccc(NC(=O)/C(=N/OC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)cc1
Reaction time: 2 h
Yield: 74.7 %

Procedure:
(E)-(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 157 mg, 0.45 mmol), 4-(3-amino-pyrazol-1-ylmethyl)-benzoic acid methyl ester (117 mg, 0.50 mmol) and N,N-diisopropylethylamine (237 μL, 1.36 mmol) were combined in methylene chloride (20 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (173 mg, 0.45 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford (E)-4-{3-[2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-acetylamino]-pyrazol-1-ylmethyl}-benzoic acid methyl ester (188 mg, 74%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C26H27ClN4O6S [M+] 558.13, found 559 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.63 (m, 4 H, 2×CH2), 1.85 (m, 4 H, 2×CH2), 3.29 (s, 3 H, SO2CH3), 3.92 (s, 3 H, CO2CH3), 4.86 (m, 1 H, OCH), 5.29 (s, 2H, NCH2), 6.79 (d, J=2.3 Hz, 1 H, Ar), 7.23 (d, J=8.3 Hz, 2 H, Ar), 7.40 (d, J=2.3 Hz, 1 H, Ar), 7.55 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.65 (d, Jm=1.5 Hz, 1 H, Ar), 8.02 (d, J=8.3 Hz, 2 H, Ar), 8.18 (d, Jo=8.2 Hz, 1 H, Ar), 9.20 (s, 1 H, NH).
Reaction SMILES: [N:1]([C@H:4]1[C:7](=[O:8])[N:6]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C@@H:5]1[C:16]([OH:18])=[O:17])=[N+:2]=[N-:3].CO.[CH2:21]1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]([C@H:4]1[C:7](=[O:8])[N:6]([Si:9]([C:12]([CH3:14])([CH3:15])[CH3:13])([CH3:11])[CH3:10])[C@@H:5]1[C:16]([O:18][CH3:21])=[O:17])=[N+:2]=[N-:3]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@H](N=[N+]=[N-])[C@H]1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H]1[C@@H](N=[N+]=[N-])C(=O)N1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude 131 (1.58 g) in CH2Cl2 (25 mL) was added methanol (0.26 mL, 6.43 mmol). DCC (1.45 g, 7.02 mmol) and catalytic DMAP. The solution was stirred at room temperature overnight. The solution was then filtered through Celite and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with 20% EtOAc in hexanes, to yield pure 132.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]>>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][C@@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=3)=[N:5]2)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)[nH]n1
Yield: 20.6 %

Procedure:
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.22 g, 0.55 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylic acid (0.17 g, 1.11 mmol) using the method of Example 34(d). Crude product was purified by CombiFlash (column: C-18, eluent: 0-100% MeCN in water) to yield 47 mg (21%) of the title compound. 1H-NMR (400 MHz; MeOD): δ 1.28 (d, 3H), 2.51 (s, 3H), 4.31 (dd, 1H), 4.41 (dd, 1H), 4.52-4.61 (m, 1H), 6.79 (d, 1H), 7.23 (s, 1H), 7.67 (d, 1H), 7.70 (d, 1H), 7.83 (m, 1H).
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][C:23]2=[O:28])=[CH:18][CH:17]=1>C(O)CC(C)C>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:27][CH2:26][N:25]([C:3]3[NH:12][C:11](=[O:13])[C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=4[N:4]=3)[CH2:24][C:23]2=[O:28])=[CH:20][CH:21]=1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Reactant: COc1ccc(N2CCNCC2=O)cc1
Solvent: CC(C)CCO
Product: COc1ccc(N2CCN(c3nc4c(c(=O)[nH]3)CCCC4)CC2=O)cc1

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol) and 1-(4-methoxyphenyl)piperazin-2-one (105 mg; 0.51 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 (reaction time 4 h) and worked up. The crude product obtained in this way is purified by column chromatography; yield: 8 mg (4%), crystals; HPLC method P; RT/min 2,87.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[O:14][CH2:15][C:16]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[N:7]3[C:8]=2[C:3]=1[C:4](=[O:24])[C:5]([C:21]([OH:23])=[O:22])=[CH:6]3.[CH3:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([NH:36][CH2:37][CH2:38][NH2:39])[CH:27]=1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:39][CH2:38][CH2:37][NH:36][C:28]2[CH:27]=[C:26]([CH3:25])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)[C:9]2[O:14][CH2:15][C:16]3([CH2:17][CH2:18][CH2:19][CH2:20]3)[N:7]3[C:8]=2[C:3]=1[C:4](=[O:24])[C:5]([C:21]([OH:23])=[O:22])=[CH:6]3
Reactant: Cc1cc(NCCN)nc2ccccc12
Reactant: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3C1(CCCC1)CO2
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(NCCNc2c(F)c(N)c3c(=O)c(C(=O)O)cn4c3c2OCC42CCCC2)nc2ccccc12
Yield: 3.9 %

Procedure:
A solution of 8-amino-9,10-difluoro-7-oxo-2,7-dihydrospiro[[1,4]oxazino[2,3,4-ij]-quinoline-3,1′-cyclopentane]-6-carboxylic acid (13 mg, 0.04 mmol) and N1-(4-methylquinolin-2-yl)ethane-1,2-diamine (10 mg, 0.05 mmol) and 11 μL triethylamine in DMSO (0.3 mL) was stirred at 90° C. for 72 h. The reaction mixture was cooled and freeze-dried overnight. The crude product was taken up in CH2Cl2 and purified by preparative TLC to yield 8-amino-9-fluoro-10-(2-(4-methylquinolin-2-ylamino)ethylamino)-7-oxo-2,7-dihydrospiro[[1,4]oxazino[2,3,4-ij]quinoline-3,1′-cyclopentane]-6-carboxylic acid (0.8 mg, 4%) as a yellow solid. MS (EP) m/z: 518 (M++1). (Calcd. for C28H28FN5O4, 517.21).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]2[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[NH:15][C:14]=2[CH:22]=O)[CH2:6][CH2:5]1.OC1CCN(CCCC2C3CCCCC=3NC=2C=O)CC1.[CH2:45]([S:47]([C:50]1[CH:51]=[C:52]2[C:56](=[CH:57][CH:58]=1)[NH:55][C:54](=[O:59])[CH2:53]2)(=[O:49])=[O:48])[CH3:46]>>[CH2:45]([S:47]([C:50]1[CH:51]=[C:52]2[C:56](=[CH:57][CH:58]=1)[NH:55][C:54](=[O:59])/[C:53]/2=[CH:22]\[C:14]1[NH:15][C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=2[C:13]=1[CH2:12][CH2:11][CH2:10][N:7]1[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[CH2:9][CH2:8]1)(=[O:48])=[O:49])[CH3:46]
Reactant: CCS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]c2c(c1CCCN1CCN(CCO)CC1)CCCC2
Agent: O=Cc1[nH]c2c(c1CCCN1CCC(O)CC1)CCCC2
Product: CCS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCN(CCO)CC1)CCCC3)C(=O)N2
Yield: 59.8 %

Procedure:
3-{3-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]- propyl}-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (64 mg, 0.2 mmol), prepared by following the procedure described for 3-[3-(4-hydroxy-piperidin-1-yl)- propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (example 20), was condensed with 5-ethylsulfonyloxindole (Example 5) (69 mg, 0.2 mmol, 65%pure). The reaction solution was purified by flash chromatography, eluting with dichloromethane/methanol (20/1, 15/1 then 10/1) to provide 63 mg of the desired compound.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=[O:2].C(=O)(O)[O-].[Na+].I[CH2:18][CH3:19]>CN(C)C=O.O>[CH:6]([C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[C:1]([O:3][CH2:18][CH3:19])=[O:2])=[O:7]
Reactant: CCI
Reactant: O=Cc1ccccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
2-Carboxybenzaldehyde (2.018g, 13.4 mmol, 1.0 eq.) was combined with sodium bicarbonate (2.258 g, 26.9 mmol, 2.0 eq.) and iodoethane (2.15 ml, 26.9 mmol, 2.0 eq.) in dimethylformamide (13.4 ml, 1M) and stirred at room temperature for 16 hours. The reaction was diluted with water (25 ml) and extracted with ether: hexane (1:1, 3X20 ml). The combined organic extracts were washed with aqueous 10% sodium bisulfite (1X25 ml), water (1X25 ml) and aqueous saturated sodium chloride (1X25 ml), dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographed on Merck silica gel (20 g) eluting with hexane: ether (14:1) to provide the title A compound (1.485 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[N:6]=[CH:5]2.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C=O)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[N:6]=[CH:5]2)[CH3:32]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3cc(O)ccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc2c(cnn2C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of tert-butyl 4-(5-hydroxy-1H-indazol-1-yl)piperidine-1-carboxylate (150 mg, 0.458 mmol) in DMF (10 mL) at 0° C. was added NaH (60% in mineral oil) (16.8 mg, 0.706 mmol) and ethyl 2-bromoacetate (119 mg, 0.706 mmol). The mixture was stirred at 25° C. for 3 h, poured into water, and the product extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4, concentrated under reduced pressure and purified by TLC (Pet.Ether:EtOAc=1:1) to give tert-butyl 4-(5-(2-ethoxy-2-oxoethoxy)-1H-indazol-1-yl)piperidine-1-carboxylate (120 mg, yield 65%) as a colorless oil. LCMS (m/z): 404.2 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2([C:28](O)=[O:29])[CH2:27][CH2:26]2)=[O:24])=[CH:18][CH:17]=1.[C:31]([O:35][C:36](=[O:46])[NH:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42](N)=[CH:41][CH:40]=1)([CH3:34])([CH3:33])[CH3:32].C[N:48](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O.CC(N(C)C)=O>[C:31]([O:35][C:36](=[O:46])[NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([NH:48][C:28]([C:25]2([C:23](=[O:24])[NH:22][C:19]3[CH:18]=[CH:17][C:16]([O:15][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][CH:7]=4)=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)=[O:29])[CH:40]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)cc3)c2cc1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5cccc(CNC(=O)OC(C)(C)C)c5)CC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]-cyclopropanecarboxylic acid (254 mg, 0.62 mmol), (4-amino-benzyl)-carbamic acid tert-butyl ester (164 mg, 0.74 mmol), dry DMA (10 mls), HATU (714 mg, 1.88 mmol), and DIEA (325 ml, 1.86 mmol) were combined and stirred at room temperature. After 2 hrs, the reaction mixture is diluted with H2O and the resulting solids are filtered, washed with H2O, followed by sat'd NaHCO3, and dried under high vacuum to give crude [3-({1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]-cyclopropanecarbonyl}-amino)-benzyl]-carbamic acid tert-butyl ester (301 mg, 79% yield) which was used in the next reaction without further purification. LC/MS Calcd for [M+H]+ 613.3. found 613.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH:14]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:24]4[C:33]5[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[CH:20][CH:21]=3)[CH3:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(N2CCN(C(C)c3ccc(N)cc3)CC2)cc1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Product: Cc1ccc(N2CCN(C(C)c3ccc(Nc4ccnc5cc(Cl)ccc45)cc3)CC2)cc1

Procedure:
In the manner given in Example 1C, 1-(p-methylphenyl)-4-[1-(p-aminophenyl)ethyl]piperazine and 4,7-dichloroquinoline are reacted together at reflux to give 4-[[4-[1-[4-(p-methylphenyl)-1-piperazinyl]ethyl]phenyl]amino]-7-chloroquinoline.
Reaction SMILES: [C:1]1([S:7][C:8]2[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[CH:26]([CH:30]([CH3:32])[CH3:31])[C:27](O)=[O:28]>>[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[CH:26]([CH:30]([CH3:32])[CH3:31])[C:27]([O:15][CH2:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:13]=1)=[O:28]
Reactant: CC(C)C(C(=O)O)c1ccc2ccccc2c1
Reactant: OCc1cccc(Sc2ccccc2)n1
Product: CC(C)C(C(=O)OCc1cccc(Sc2ccccc2)n1)c1ccc2ccccc2c1

Procedure:
Following the procedure of Example 3, (6-phenylthio-2-pyridyl)methanol and 2-(2-naphthyl)-3-methylbutanoic acid are reacted to give (6-phenylthio-2-pyridyl)methyl 2-(2-naphthyl)-3-methylbutanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:19]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16])=O.BrC1C=C(Cl)C=CC=1[O:29][CH2:30][O:31][CH2:32][CH2:33]OC.FC(F)(F)C1C=CC=C[C:39]=1[CH:40]=[O:41]>>[CH2:32]([O:31][C:30]([C:39]1[C:40](=[O:41])[O:20][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][C:6]=2[C:7]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16])=[O:29])[CH3:33]
Reactant: COCCOCOc1ccc(Cl)cc1Br
Reactant: O=C(c1cc(Cl)ccc1O)c1ccccc1C(F)(F)F
Reactant: O=Cc1ccccc1C(F)(F)F
Product: CCOC(=O)c1c(-c2ccccc2C(F)(F)F)c2cc(Cl)ccc2oc1=O

Procedure:
5-Chloro-2-hydroxy-2'-(trifluoromethyl)benzophenone [prepared from 2-bromo-4-chloro-(2-methyoxyethoxy)methoxybenzene and ortho-(trifluoromethyl)benzaldehyde as the starting materials: melting point, 71°-72° C. (recrystallized from hexane-isopropyl ether)] was reacted by a method similar to Process 1 of Reference Example 25 to yield 6-chloro-2-oxo-4-[2-(trifluoromethyl)phenyl)-2H-1-benzopyran-3-carboxylic acid ethyl ester as an oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[O:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CO.Cl[CH2:19][N:20]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][C:26]([O:35][CH3:36])=[CH:27][C:28]=2[CH:32]([CH3:34])[CH3:33])[S:21]1(=[O:23])=[O:22]>O>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:19][N:20]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[CH:27][C:28]=3[CH:32]([CH3:34])[CH3:33])[S:21]2(=[O:22])=[O:23])=[O:8])[O:4][N:3]=1
Reactant: Cc1cc(C(=O)O)on1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COC(=O)c1cc(C)no1)C2=O
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
A mixture of 3-methylisoxazole-5-carboxylic acid (0.63 g, 5.0 mmol), cesium carbonate (0.8 g, 2.45 mmol) and methanol was stirred for 30 minutes. The solvent was removed in vacuo and the residue was dried in high vacuum for 1 hour. The residue was suspended in DMF (30 ml) and 2-chloromethyl-4-isopropyl-6-methoxysaccharin (1.0 g, 3.3 mmol) was added. The mixture was stirred at room temperature for 19 hours and was poured into water. The mixture was extracted with ethyl acetate/ether (4/1, 300 ml) and the organic layer was separated and wash with water, then brine. The solvent was removed in vacuo and the residue was purified by flash chromatography (30% ethyl acetate/hexanes) to afford 1.1 g (85%) of 4-isopropyl-6-methoxy-2-saccharinylmethyl 3-methylisoxazole-5-carboxylate as a white powder, m.p. 157°-158° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[C:7]([CH3:24])[C:6]=2[C:5]([OH:25])=[CH:4][CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][C:39](=[O:42])[CH2:40]Br>C(OCC)(=O)C>[CH3:37][O:38][C:39](=[O:42])[CH2:40][O:25][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:24])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][CH:15]=1)[C:9]([CH3:12])=[N:10]2
Reactant: Cc1nc2c(Cl)ccc(O)c2c(C)c1Cc1ccc(S(C)(=O)=O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(S(C)(=O)=O)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 8-chloro-3-(4-methanesulfonylbenzyl)-2,4-dimethylquinolin-5-ol (0.31 g), N,N-dimethylformamide (5.0 mL), potassium carbonate (0.46 g) and bromoacetic acid methyl ester (0.35 g) was stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate and this solution washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of toluene, dichloromethane and ethyl acetate (1:1:0 to 0:1:0 and 0:1:1 by volume) gave title compound as a white solid, 0.20 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=O.Cl.[NH2:12][OH:13].[OH-].[Na+].Cl>C(OCC)C.C(O)C.O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=[N:12][OH:13]
Reactant: NO
Reactant: O=Cc1c(Cl)cncc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: ON=Cc1c(Cl)cncc1Cl
Temperature: 0 °C
Yield: 98.2 %

Procedure:
Combine 3,5-dichloropyridine-4-carboxaldehyde (2.80 g, 0.016 mol) with hydroxylamine hydrochloride (1.13 g, 0.018 mol) and ice (50 g) in an ethanol/water (30 mL/30 mL) mixture. Add aqueous sodium hydroxide (1.63 g, 0.024 mol, in 20 mL of water) dropwise and stir for 4 h near ambient temperature. Adjust the mixture to approx. pH 7.0 with aqueous hydrochloric acid and extracte with diethyl ether. Dry the combined extracts over sodium sulfate and concentrate in vacuo to give the desired crude oxime (3.00 g, 88%) as a light solid. MS(ES): (M+1)+ 190.9, 192.9 m/z.
Reaction SMILES: [ClH:1].[CH2:2]([N:6]1[C:11]2([CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]([OH:33])=O)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)[C:10](=[O:34])[NH:9][C@H:8]([C@H:35]([OH:42])C2CCCCC2)[C:7]1=[O:43])[CH2:3][CH2:4][CH3:5].COC([O:49][NH2:50])(C)C.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C.ON1[C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][C:76]=2N=N1.Cl>CN(C)C=O.O>[ClH:1].[CH2:2]([N:6]1[C:11]2([CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]4[CH:26]=[CH:27][C:28]([C:31](=[O:33])[NH:50][OH:49])=[CH:29][CH:30]=4)=[CH:22][CH:23]=3)[CH2:13][CH2:12]2)[C:10](=[O:34])[NH:9][C@H:8]([C@H:35]([OH:42])[CH:76]2[CH2:77][CH2:78][CH2:79][CH2:80][CH2:81]2)[C:7]1=[O:43])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN1C(=O)[C@@H]([C@H](O)C2CCCCC2)NC(=O)C12CCN(Cc1ccc(Oc3ccc(C(=O)O)cc3)cc1)CC2
Reactant: COC(C)(C)ON
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1C(=O)[C@@H]([C@H](O)C2CCCCC2)NC(=O)C12CCN(Cc1ccc(Oc3ccc(C(=O)NO)cc3)cc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a suspension of the compound prepared in Example 9(54) (120 mg) and (1-methoxyisopropyl)oxyamine (31 mg) in dimethylformamide (1.6 ml) was added diisopropylethylamine (68 μl), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide.hydrochloride (56 mg) and 1-hydroxybenztriazole (40 mg). The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was added 1N hydrochloric acid (2 ml) and stirred for 15 minutes at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride and the obtained residue was dried over anhydrous sodium sulfate and concentrated. To a solution of the obtained residue in methanol was added 4N hydrogen chloride/ethyl acetate solution and concentrated. The obtained residue was washed with ethyl acetate to give the title compound (116 mg) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:22])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:23][NH:24][CH2:25][CH2:26][CH2:27][OH:28].[CH3:29][CH2:30][N:31]([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33]>CC(O)C>[Br:1][C:2]1[C:3]([N:24]([CH2:25][CH2:26][CH2:27][OH:28])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:29][CH2:30][N:31]([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33].[ClH:22]
Reactant: CNCCCO
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Product: Cl
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 237 mg, 0.60 mmol), 3-(methylamino)propan-1-ol (64 mg, 0.72 mmol), iPrOH (2.4 mL) and DIPEA (0.205 mL, 0.155 g, 1.2 mmol) were subjected to MW irradiation at 140° C. for 3 h. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure. No further purification was required to afford the title compound in an equimolar mixture with DIPEA hydrochloride. LC-MS (Condition 5) tR=1.18 min, m/z=448.0 [M+H]+, m/z=446.0 [M−H]−.